RNA binding fox-1 homolog 2 (RBFOX2) is a regulator of alternative splicing (AS) involved in various physiological and pathological processes, but whether it could modulate metabolism is not clear. Previous work in the lab suggests that RBFOX2 is required for maintaining hepatic lipid homeostasis in liver under the influence of obesogenic diet by controlling the AS of Scarb1. Building on this, the project aims to investigate the role of RBFOX2 in metabolic regulation by studying its functions in the liver and adipose tissues.
Here, I have found that RBFOX2 controls the abundance of hepatic cholesterol, cholesteryl ester (CE) and other specific species by affecting the AS of lipid re-modelling genes, such as Numb exon 3/9, Sec31a and Osbpl9. Moreover, RBFOX2 positively regulates tumourigenesis, proliferation and invasion of hepatocellular carcinoma (HCC), potentially through modulating the AS mutually exclusive ex-ons (MXEs) in Slc7a2 pre-mRNA, leading to increased efficiency in cationic amino acid transport due to the production of the low-affinity, high-efficiency isoform of solute carrier family 7 member 2 (SLC7A2), CAT-2A. In adipose tissues, I have shown that RBFOX2 promotes high-fat diet (HFD)-induced weight gain, visceral adipose tissue expansion and food intake, and negatively regulates body temperature in cold exposure in association with low UCP1 expression in brown adipose tissue (BAT). Similar to that in liver, RBFOX2 mod-ulates the AS of a number of genes involved in metabolic regulation in adipose tissues, including Scarb1, Pla2g6, Numb, Ogdh and Tsc2.
Although more work is still required for understanding these mechanisms in detail, the data shown in this dissertation have suggested a novel role of RBFOX2 in metabolic regulation, in liver and adipose tissue, and have proposed the therapeutic potential of targeting RBFOX2-mediated AS events for the treatment of cancer and other metabolic disorders.